The present invention relates generally to systems or methods of using such systems to calculate the radiation dose received by circulating blood cells during a course of external beam radiotherapy. The present invention also discloses systems or methods of applying such systems to identify circulating blood as an organ at risk in radiation therapy.
Marked reductions in the lymphocyte count are common following therapy for malignant glioma and can have significant clinical consequences. Severe lymphopenia in this setting has been associated with serious opportunistic infections [Mahindra A K, Grossman S A. Pneumocystis carinii pneumonia in HIV negative patients with primary brain tumors. J Neurooncol 2003; 63(3):263-270; Meije Y, Lizasoain M, Garcia-Reyne A, et al. Emergence of cytomegalovirus disease in patients receiving temozolomide: report of two cases and literature review. Clin Infect Dis 2010; 50(12):e73-e76. doi: 10.1086/653011]. Perhaps more importantly, emerging data from patients with malignant gliomas and pancreatic cancer demonstrate that patients with severe treatment-induced lymphopenia have significantly worse survival and die from early tumor progression [Balmanoukian A, Ye X, Herman J, Laheru D, Grossman S. Effect of treatment-related lymphopenia on survival in newly diagnosed patients with adenocarcinoma of the pancreas. Clin Invest 2012; In press; Grossman S A, Ye X, Lesser G, et al. Immunosuppression in patients with high-grade gliomas treated with radiation and temozolomide. Clin Cancer Res 2011; 17(16):5473-5480. doi: 10.1158/1078-0432.CCR-11-0774; 10.1158/1078-0432.CCR-11-0774]. Interest in treatment-induced lymphopenia was sparked by a cluster of Pneumocystis jiroveci pneumonia cases, associated with extremely low CD4 counts, in patients treated with radiation therapy and steroids (without chemotherapy) for brain tumors (Mahindra A K, Grossman S A. Pneumocystis carinii pneumonia in HIV negative patients with primary brain tumors. J Neuro Oncol 2003; 63(3):263-270). This led to a prospective study of serial total lymphocyte and CD4 counts in brain tumor patients receiving radiation and corticosteroids. This demonstrated that CD4 counts were >450/μL in all patients before starting therapy, but that during treatment, approximately one-fourth developed CD4 counts <200/μL [Hughes M A, Parisi M, Grossman S, Kleinberg L. Primary brain tumors treated with steroids and radiotherapy: Low CD4 counts and risk of infection. Int J Radiat Oncol Biol Phys 2005; 62(5):1423-1426. doi: 10.1016/j.ijrobp.2004.12.085]. After temozolomide became standard therapy, a second study prospectively evaluated serial lymphocyte counts in high-grade glioma patients receiving radiation and temozolomide. In this study, over 40% of patients developed CD4 lymphocyte counts under 200/μL 2 months after completing treatment and over 70% had CD4 counts under 300/μL. Participants with CD4 counts <200/μL 2 months after initiating radiation and temozolomide had significantly worse overall survival than those with higher CD4 counts [Grossman S A, Ye X, Lesser G, et al. Immunosuppression in patients with high-grade gliomas treated with radiation and temozolomide. Clin Cancer Res 2011; 17(16):5473-5480. doi: 10.1158/1078-0432.CCR-11-0774; 10.1158/1078-0432.CCR-11-0774].
Although patients with malignant glioma receive a triad of lymphotoxic agents (corticosteroids, temozolomide, and radiation therapy), radiation may play an important role in lymphopenia. Lymphopenia following radiation therapy was first described in the early 20th century, only a few years after x-rays were discovered, and has since been documented to occur after either external beam radiotherapy or brachytherapy directed to virtually every part of the body [Shohan J. Some theoretical considerations on the present status of roentgen therapy. N Engl J Med 1916; 175:321-327]. Radiation can induce lymphopenia regardless of whether chemotherapy or steroids are given concurrently or whether bone marrow or lymphatic tissue is included in the field. For example, irradiation of the brain, which contains neither bone marrow nor lymphatic tissue, can cause over a 60% reduction in the lymphocyte count [MacLennan I C, Kay H E. Analysis of treatment in childhood leukemia. IV. The critical association between dose fractionation and immunosuppression induced by cranial irradiation. Cancer 1978; 41(1):108-111]. Furthermore, even radiation of extracorporeal blood in patients undergoing renal dialysis can result in profound and durable lymphopenia [Weeke E. The development of lymphopenia in uremic patients undergoing extracorporeal irradiation of the blood with portable beta units. Radiat Res 1973; 56(3):554-559]. These observations suggest that irradiation of circulating lymphocytes may contribute to the development of radiation-induced lymphopenia.
Calculating radiation dose to circulating blood is challenging and is affected by many parameters, including target volume size, radiation treatment technique, dose rate, total dose, fraction size, treatment time, the speed of circulating blood, and the presence or absence of major vasculature in or near the radiation field. Presently, although circulating blood cells are an organ at risk for toxicity due to radiation therapy, there are no commercially available systems to calculate the dose to circulating blood. Needed in the art are methods and systems for calculating the dose received by circulating blood during a course of external beam radiotherapy.